THE MANY WAYS OF WAKING UP FROM SLEEP - MOVING FORWARD THE ANALYSIS OF SLEEP MICROARCHITECTURE

One of the defining characteristics of sleep is that it is readily reversible towards wakefulness. This is exemplified in the common daily experience of waking up in the morning. My thesis studies sleep-wake transitions that are equally common and frequent, yet often not consciously perceived and neglected as random sleep perturbations of minor significance. Using mice as an experimental species, I find that healthy non-rapid-eye-movement sleep (NREMS), also named deep restorative sleep, is a dynamic brain state showing defined, periodically recurring moments of fragility. During these, diverse types of brief arousal-like events with various combinations of physiological correlates appear, including global or local cortical activation, muscle activity, and heart rate changes. Using a mice model of chronic neuropathic pain, I find that the rules I have identified in healthy sleep serve to identify previously unrecognized sleep disruptions that could contribute to sleep complaints of chronic pain patients. The experimental and analytical methods I have developed in these studies also helped in the identification of the neuronal basis of the fragility periods of NREM sleep. Together, my studies offer novel insights and analytical tools for the study of sleep-wake transitions and their perturbance in pathological conditions linked to sensory discomfort. More specifically, my work departed from recent findings that NREMS in mice is divided in recurring periods of sleep fragility at frequencies ~0.02 Hz, characterized by heightened arousability. Through analyzing the temporal distribution of brief arousal events termed microarousals, I hypothesized that these fragility periods could serve a time raster for the probing of spontaneous sleep perturbations. Motivated by the question of how sensory discomfort caused by pain affects sleep, I have used the spared nerve injury (SNI) model, which consists in the injury of two of the 3 branches of the sciatic nerve. I found that the role of fragility periods in timing spontaneous arousals is highly useful to identify sleep disruptions not commonly detected with standard polysomnographic measures. Thus, by scrutinizing the fragility periods of NREMS in the SNI mice, I discovered an overrepresentation of a novel form of local perturbation within the hindlimb primary somatosensory cortex (S1HL), accompanied by heart rate increases. In addition, I showed that SNI animals woke up more frequently facing external stimuli, using closed-loop methods targeting specifically the fragility or continuity periods. These findings led me to propose that chronic pain-related sleep complaints may arise primarily from a perturbed arousability. The closed-loop techniques to probe arousability could be transferred to interrogate neuronal mechanisms underlying NREMS fragility, leading to the recognition that intrusion of wake-related activity into NREMS is a previously underappreciated mechanism controlling sleep fragility and architecture. Overall, I present my thesis to advance the view on NREMS as a dynamic heterogeneous state of which insights into its neuronal mechanisms, and its physio- and pathophysiological manifestations in animal models should be key to formulate testable hypotheses aimed to cure the suffering of sleep disorder in human. -- Une des caractéristiques qui définit le sommeil, est que l’on peut rapidement retourner à un état d’éveil. De fait, nous l’expérimentons chaque matin au réveil. Ma thèse étudie les transitions sommeil-éveil qui, bien que fréquentes, sont souvent non consciemment perçues et traitées comme des perturbations sans importance et aléatoires du sommeil. En utilisant la souris comme modèle expérimental, je montre que le sommeil sans mouvements rapides des yeux (NREMS), également appelé le sommeil profond et réparateur, est un état cérébral dynamique composé de périodes discrètes et récurrentes de fragilité face à des stimuli externe. Pendant celles-ci, plusieurs types d’évènements associés à des éveils brefs apparaissent, combinant activation corticale, activité musculaire et/ou une hausse des battements cardiaques. Je démontre que la compréhension des transitions sommeil-éveil physiologiques s’avère utile pour étudier le sommeil de souris souffrant de douleurs neuropathiques chroniques. Ces souris présentent un nouveau type de perturbations locales lors du sommeil, qui pourraient possiblement expliquer une partie des plaintes de mauvais sommeil exprimées par les patients souffrant de douleurs chroniques. Les méthodes analytiques et expérimentales que j’ai développées dans ces études ont aussi aidé à l’identification des bases neuronales de la genèse des périodes de fragilités du sommeil NREM. En somme, mes études offrent des connaissances inédites et des méthodes d’analyses pour l’étude des transitions sommeil-éveil et de leurs perturbations en conditions pathologiques. Une étude récente du laboratoire a montré que le sommeil NREM est divisé en périodes de fragilité alternant avec des périodes de non-fragilité (continuité), environ toutes les 50 secondes ce qui donne une fréquence de 0.02 Hz. Les périodes de fragilité sont caractérisées par une hausse de « l’éveillabilité » ou propension à s’éveiller. Ma première observation est que les éveils brefs, couramment appelés micro-réveils, présentent une distribution temporelle hautement restreinte aux périodes de fragilité. Ainsi, j’ai émis l’hypothèse que ces périodes pourraient servir de moments spécialement choisis par le cerveau pour la mesure de potentielles perturbations spontanées. Motivé par la question de comment les douleurs chroniques perturbent le sommeil, je l’ai analysé chez un modèle de souris de douleurs neuropathique, le modèle de d’épargne du nerf sural (SNI). Le rôle des périodes de fragilité à restreindre les micro- réveils s’est avéré très utile pour détecter de nouvelles formes de réaction à des perturbations qui ne sont pas évidentes par des analyses classiques du sommeil. En effet, spécifiquement pendant ces périodes de fragilité, j’ai découvert une sur-représentation d’un nouveau type d’éveil local confiné au cortex somatosensoriel primaire et accompagné d’une hausse du rythme cardiaque. De plus, en utilisant de nouvelles méthodes basées sur des boucles-fermées, j’ai démontré que les souris SNI se réveillaient plus fréquemment que leurs contrôles en faisant face à des stimuli externes. Sur la base de ces découvertes, je propose que les plaintes de mauvais sommeil chez les patients souffrant de douleurs chroniques puissent prendre leur source dans une éveillabilité perturbée. Les méthodes de boucles-fermées pour analyser l’éveillabilité a aussi pu être transférée pour l’étude optogénétique des mécanismes neuronaux à la base de la fragilité du sommeil NREM. Cela a mené à la reconnaissance que l’intrusion d’activité normalement associée à l’éveil dans le sommeil est un mécanisme de contrôle de sa fragilité et de son architecture souvent ignoré dans le domaine. En somme, ma thèse permet une avancée de notre vision du sommeil NREM comme étant un état dynamique et hétérogène dont les mécanismes neuronaux sous-jacent, en conditions normales et pathogéniques, sont clefs pour la formulation d’hypothèses testables visant à la guérison des patients souffrant de troubles du sommeil

Cortico-autonomic local arousals and heightened somatosensory arousability during NREMS of mice in neuropathic pain.

Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid eye movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared nerve injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability

Combining Leakage-Resilient PRFs and Shuffling Towards Bounded Security for Small Embedded Devices

Combining countermeasures is usually assumed to be the best way to protect embedded devices against side-channel attacks. These combinations are at least expected to increase the number of measurements of successful attacks to some reasonable extent, and at best to guarantee a bounded time complexity independent of the number of measurements. This latter guarantee, only possible in the context of leakage resilient constructions, was only reached either for stateful (pseudo-random generator) constructions, or large parallel implementations so far. In this paper, we describe a first proposal of stateless (pseudo-random function) construction, for which we have strong hints that security bounded implementations are reachable under the constraints of small embedded devices. Our proposal essentially combines the well-known shuffling countermeasure with a tweaked pseudo-random function introduced at CHES 2012.We rst detail is performances. Then we analyze it against standard differential power analysis and discuss the different parameters influencing its security bounds. Finally, we put forward that its implementation in 8-bit microcontrollers can provide a better security vs. performance tradeo than state-of-the art (combinations of) countermeasures

Key Enumeration from the Adversarial Viewpoint: When to Stop Measuring and Start Enumerating?

In this work, we formulate and investigate a pragmatic question related to practical side-channel attacks complemented with key enumeration. In a real attack scenario, after an attacker has extracted side-channel information, it is possible that despite the entropy of the key has been significantly reduced, she cannot yet achieve a direct key recovery. If the correct key lies within a sufficiently small set of most probable keys, it can then be recovered with a plaintext and the corresponding ciphertext, by performing enumeration. Our proposal relates to the following question: how does an attacker know when to stop acquiring side-channel observations and when to start enumerating with a given computational effort? Since key enumeration is an expensive (i.e. time-consuming) task, this is an important question from an adversarial viewpoint. To answer this question, we present an efficient (heuristic) way to perform key-less rank estimation, based on simple entropy estimations using histograms

Connecting and Improving Direct Sum Masking and Inner Product Masking

Direct Sum Masking (DSM) and Inner Product (IP) masking are two types of countermeasures that have been introduced as alternatives to simpler (e.g., additive) masking schemes to protect cryptographic implementations against side-channel analysis. In this paper, we first show that IP masking can be written as a particular case of DSM. We then analyze the improved security properties that these (more complex) encodings can provide over Boolean masking. For this purpose, we introduce a slight variation of the probing model, which allows us to provide a simple explanation to the “security order amplification” for such masking schemes that was put forward at CARDIS 2016. We then use our model to search for new instances of masking schemes that optimize this security order amplification. We finally discuss the relevance of this security order amplification (and its underlying assumption of linear leakages) based on an experimental case study